1. INTRODUCTION:

India continues to be the "diabetes capital" of the world and about 63 million people suffer from diabetes, and this figure is likely to go up to 80 million by 2025. Delhi alone has more than 30 lacks people suffering from this disease. India accounts for the largest number of people suffering from diabetes in the world, followed by China (43.2 million) and the United States (26.8 million).

Diabetes mellitus is a disorder in which the level of blood glucose is determinedly raised above the normal range. It occurs because of lack of insulin, with or without factors that oppose the action of insulin. Hyperglycaemia results from insufficient insulin action. There are many associated metabolic abnormalities, notably the development of Hyperketonaemia when there is severe lack of insulin, together with alteration of fatty acid, lipid and protein turnover and there is also change in haemorheological factors and oxidant status. Mainly there are two types of diabetes, Type 1 diabetes and Type 2 diabetes^{1, 2}.

Both Type 1 diabetes and Type 2 diabetes have a genetic predisposition, which is more obvious in the case of Type2 diabetes. Destruction of pancreas by chronic pancreatitis, haemochromatosis or carcinoma results in diabetes. Other endocrine disorders, such as Cushing’s syndrome, hyperpituitarism and hyperthyroidism, are associated with the disease. Glucose intolerance occurs during pregnancy or times of excessive stress and with administration of glucocorticoides, thiazides and oral contraceptives^{3, 4}.

2. PATHOPHYSIOLOGY:

The beta cells of pancreas are decreased in number or are degranulated in diabetes. The reduction in number of beta cells corresponds to the lack of insulin. In Type1 diabetes there are no beta cells, in Type 2 diabetes only about one half of them are present. In some cases these cells are infiltrated with lymphocytes, suggesting an autoimmune mechanism for Type1 diabetes. The presence of anti-islet antibodies also supports an autoimmune hypothesis in type1 diabetes. The atherosclerosis that occurs in diabetes occurs as frequently on females as males and at an earlier age. In the Kidney glomerulosclerosis is seen, which is the deposition of glycoprotein in the mesangium, also is seen, as well as tubular basement membrane thickening. The earliest finding of diabetic neuropathy is micro aneurysms. Proliferative retinopathy, the formation of new blood vessels around optic disk, occurs with long standing diabetes. Repeated hemorrhages formation cause scar formation that may lead to retinal detachment. The changes of hypertensive retinopathy also are seen in diabetics with hypertension⁵.

The lack of insulin results in a peripheral under utilization and a hepatic over production of glucose which results in hyperglycemia. Insulin facilitates the entry of glucose into the cells of adipose tissue and muscle, stimulates fat synthesis in cells and protein synthesis. The lack of glucose in muscle cell leads to glycogenolysis and the release of amino acids for gluconeogenesis. Deficiency of insulin and glucose in adipose tissue leads to impaired triglyceride synthesis and release of fatty acids. The liver metabolizes free fatty acids to ketones which are used by muscles for energy, to certain extent. Lack of insulin also results in hepatic over production of glucose from glycogenolysis and gluconeogenesis⁶.

Hyperglycemia results in glucosuria when the serum level of glucose exceeds the renal threshold for reabsorbtion of glucose. The osmotic diuresis results in polyuria and polydipsia and may result in dehydration. Excess ketones also are excreted in urine, as strong acids. This results in urinary loss of bicarbonates and potassium and dehydration.

Normally insulin is released on response to glucose load such as carbohydrate containing meal. Serum insulin level rises within 15 to 20 min after eating. Patients with Type 1 diabetes do not produce insulin. Those with Type 2 diabetes produce too little insulin too late to prevent hyperglycemia. Obese people have hypertrophied adipose cells, which because of their size, less sensitive to insulin action.

The vascular complication of diabetes mellitus is related to hyperglycemia. It is postulated that glycoprotein is deposited in capillaries when glucose levels are elevated. Formation of cataract and neuropathy are thought to occur because glucose is metabolized to sorbitol by aldose reductase in hyperglycemia. The sorbitol causes osmotic swelling and damage⁷.

3. CLASSIFICATION:

According to World Health Organization (WHO) diabetes has been Classified in following type:

I. Type 1 diabetes (insulin dependent diabetes) is caused by ß cell destruction, usually leading to absolute insulin deficiency.

A. Immune mediated

B. Idiopathic

II. Type 2 diabetes (non insulin dependent diabetes) ranges from those with predominant insulin resistance associated with relative insulin deficiency, to those with a predominantly insulin secretary defect with insulin resistance.

III. Some other specific types

Genetic defects of beta cell function

Chromosome 12 HNF-1 alpha (formerly MODY 3)

Chromosome 7 glucokinase defect (formerly MODY 2)

Chromosome 20 HNF-4alpha (formerly MODY 1)

Insulin promoter factor 1 (formerly MODY 4)

Disease of the exocrine pancreas

Pancreatitis

Pancreactectomy

Carcinoma of pancreas

Cystic fibrosis

Fibrocalculous pancreatopathy

Drug induced

Corticosteriods

Diazoxide

Alpha interferon

4. EPIDEMIOLOGY:

Diabetes is a global disease with a huge adverse impact on health and mortality, particularly from cardiovascular disorders. It occurs at any time of life from infancy to old age. Type 2 diabetes is primarily a lifestyle disorder which accounts for around 90 % of cases. It is increasing at an astonishing rate, particularly in developing countries, presenting serious logistical problems regarding the resources needed to improve the outlook of these patients. Type 1 diabetes is primarily an autoimmune disorder, and its incidence is increasing in northern European countries at an average rate of 3 % per year, for very different reasons. The prevalence of both major forms of diabetes varies greatly from one part of the world to another, so that there are some areas where one or other scarcely exists while in others more than half of adult population can be shown to have Type 2 diabetes⁸.

5. SIGNS AND SYMPTOMS:

The classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be delicate or absent in type 2 diabetes.

Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes^10,
11.

6. PATHOPHYSIOLOGY OF TYPE-1 DIABETES:

The autoimmune destruction of pancreatic ß-cells leads to a deficiency of insulin secretion. It is this loss of insulin secretion that leads to the metabolic derangements associated with insulin dependent diabetes mellitus (IDDM). In addition to the loss of insulin secretion, the function of pancreatic γ-cells is also abnormal. There is excessive secretion of glucagon in IDDM patients. Normally, hyperglycemia leads to reduced glucagon secretion. However, in patients with IDDM, glucagon secretion is not suppressed by hyperglycemia. The resultant improperly elevated glucagon levels exacerbate the metabolic defects due to insulin deficiency. The most pronounced example of this metabolic disruption is that patients with IDDM rapidly develop diabetic ketoacidosis in the absence of insulin administration. If somatostatin is administered to suppress glucagon secretion, there is a concomitant suppression in the rise of glucose and ketone bodies. Particularly problematic for long term IDDM patients is an impaired ability to secrete glucagon in response to hypoglycemia. This leads to potentially fatal hypoglycemia in response to insulin treatment in these patients¹².

Although insulin deficiency is the primary defect in IDDM, in patients with poorly controlled IDDM there is also a defect in the ability of target tissues to respond to the administration of insulin. There are multiple biochemical mechanisms that account for this impairment of tissues to respond to insulin. Deficiency in insulin leads to elevated levels of free fatty acids in the plasma as a result of uncontrolled lipolysis in adipose tissue. Free fatty acids suppress glucose metabolism in peripheral tissues such as skeletal muscle. This impairs the action of insulin in these tissues, i.e. the promotion of glucose utilization. Additionally, insulin deficiency decreases the expression of a number of genes necessary for target tissues to respond normally to insulin such as glucokinase in liver and the GLUT 4 class of glucose transporters in adipose tissue. The major metabolic derangements which result from insulin deficiency in IDDM are impaired glucose, lipid and protein metabolism¹³.

Uncontrolled IDDM leads to increased hepatic glucose output. First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle, insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues. Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism¹⁴. In addition, the level of hepatic glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin. The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels. Glucose is an osmotic diuretic and an increase in renal loss of glucose is accompanied by loss of water and electrolytes, termed polyuria. The result of the loss of water leads to the activation of the thirst mechanism. The negative caloric balance which results from the glucosuria and tissue catabolism leads to an increase in appetite and food intake¹⁵.

One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipocytes storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues and metabolized to provide energy. Free fatty acids are also taken up by the liver¹⁶.

Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyltransferase I, the enzyme required for the transport of fatty acyl-CoA's into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA's into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, acetoacetate and hydroxybutyrate. These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the organisms’ ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor ¹⁷. Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL), an enzyme on the surface of the endothelial cells lining the vessels. In particular, LPL activity allows fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hyper triglyceridemia results¹⁸.

Insulin regulates the synthesis of many genes, either positively or negatively that then affect overall metabolism. Insulin has a global effect on protein metabolism increasing the rate of protein synthesis and decreasing the rate of protein degradation. Thus, insulin deficiency will lead to increased catabolism of protein. The increased rate of proteolysis leads to elevated concentrations in plasma amino acids. These amino acids serve as precursors for hepatic and renal gluconeogenesis. In liver, the increased gluconeogenesis further contributes to the hyperglycemia seen in IDDM¹⁹.

7. PATHOPHYSIOLOGY OF TYPE-2 DIABETES:

Unlike patients with IDDM, those with non insulin dependent diabetes mellitus (NIDDM) have detectable levels of circulating insulin. On the basis of oral glucose tolerance testing the essential elements of NIDDM can be divided into 4 distinct groups; those with normal glucose tolerance, impaired glucose tolerance (called chemical diabetes), diabetes with minimal fasting hyperglycemia (fasting plasma glucose <140 mg/dL), and diabetes mellitus in association with overt fasting hyperglycemia (fasting plasma glucose >140 mg/dL). In patients with the highest levels of plasma insulin (impaired glucose tolerance group) there was also elevated plasma glucose. This indicates that these individuals are resistant to the action of insulin. In the progression from impaired glucose tolerance to diabetes mellitus the level of insulin declines indicating that patients with NIDDM have decreased insulin secretion²⁰. Additional studies have subsequently demonstrated that both insulin resistance and insulin deficiency is common in the average NIDDM patient. Many experts conclude that insulin resistance is the primary cause of NIDDM, however, others contend that insulin deficiency is the primary cause because a moderate degree of insulin resistance is not sufficient to cause NIDDM. As indicated above, most patients with the common form of NIDDM have both defects²¹.

Recent evidence has demonstrated a role for a member of the nuclear hormone receptor super family of proteins in the etiology of type 2 diabetes. New class of drug use to increase the sensitivity of the body to insulin is the thiazolidinedione drugs. These compounds bind to and alter the function of the peroxisome proliferator activated receptor γ (PPARγ). PPARγ is also a transcription factor and, when activated, binds to another transcription factor known as the retinoid X receptor, (RXR). When these two proteins are complexed a specific set of genes becomes activated. PPARγ is a key regulator of adipocytes differentiation; it can induce the differentiation of fibroblasts or other undifferentiated cells into mature fat cells. PPARγ is also involved in the synthesis of biologically active compounds from vascular endothelial cells and immune cells²².

Mutations in the gene for PPARγ have been correlated with insulin resistance. It is still not completely clear how impaired PPAR signaling can affect the sensitivity of the body to insulin or indeed if the observed mutations are a direct or indirect cause of the symptoms of insulin resistance²³.

8. NON INVASIVE ROUTES FOR INSULIN DELIVERY:

Biologically active agents such as nutritional supplements, hormones, and a variety of pharmaceutical preparations , which will generally be referred to as "drugs` are typically provided in oral or injectable dosage formulations, however there are many disadvantages associated with this type of administration. Many of the ingredients are degraded within the gastrointestinal tract or undergo first-pass metabolism in the liver²⁴.

During the past three decades, however, formulations that control the rate and period of drug delivery and target specific areas of the body for treatment have become increasingly common and complex. Some have provided solutions to the problem of administering different types of drugs but there are still a large number of medications that do not achieve maximum pharmaceutical effect because they do not reach the intended tissue targets either fast enough or in high enough concentrations. The potency and therapeutic effects of many drugs are limited or reduced because of the partial degradation that occurs before they reach a desired target in the body^{25, 26}.

Further, injectable medications could be made less expensively and administered more easily if they could simply be dosed by other routes such as the oral mucosa, the pulmonary mucosa or through the vaginal and intestinal tract. However, this improvement cannot happen until methods are developed to safely shepherd drugs through these specific areas of the body, where different physiological environments can destroy a medication or where absorption is not rapid or complete, or through an area where healthy tissue might be adversely affected²⁷.

The goal of all drug delivery systems is to position medications intact to specifically targeted parts of the body through a medium that can control the therapy's administration by means of either a physiological or chemical trigger. To achieve this goal, a number of researchers have turned to advances in micro and nanotechnology. Various prominent areas such as buccal delivery, pulmonary delivery, aerosol inhalation devices, transdermal delivery and forced-pressure injectable and biodegradable polymer networks has been designed to transport drug^{28, 29}.

8.1 Buccal delivery:

Transmucosal routes of drug delivery offer different advantages. Mucosal linings of the nasal passages and the oral cavity are the most attractive than other route. Within the oral cavity, there are three generally recognized routes of administration of a biologically active agent. Local delivery is mainly limited to applications regarding disruptions occurring within the oral cavity itself, such as a canker sore³⁰. Sublingual delivery is achieved through the mucosal membranes lining the floor of the mouth. This route provides rapid absorption and has reached commercial status with biologically active agents such as nitroglycerin, which is placed under the tongue. Because of the high permeability and the rich blood supply, transport via the sublingual route results in a rapid onset of action, providing a delivery route appropriate for highly permeable drugs with short delivery period requirements and an infrequent dosing regimen³¹. The third generally recognized route is the buccal mucosa. This area encompasses the mucosal membranes of the inner lining of the cheeks. This area also has a rich blood supply, is robust, and provides a short cellular recovery time following stress or damage. Although the buccal mucosa is less permeable than the sublingual area, the expanse of smooth and relatively immobile mucosa provide a highly desirably absorption pathway for sustained-release and controlled-release delivery of biologically active agents^{32, 33}.

As with other transmucosal routes of administration, two major advantages include: avoiding hepatic first-pass metabolism and pre-systemic elimination within the GI tract. One of the major disadvantages associated with buccal mucosa delivery of a biologically active agent has been the relatively low passage of active agents across the mucosal epithelium, thereby resulting in low agent bioavailability, which translates into a substantial loss usable active agent within each dosage³⁴. Various permeation and absorption enhancers such as polysorbate-80, sorbitol, and phosphatidylcholine have been explored to improve buccal penetration. Studies have indicated that the superficial layers and protein domain of the epithelium may be responsible for maintaining the barrier function of the buccal mucosa³⁵. Additionally, it is known that use of a permeation enhancer can increase the passage of a biomolecules³⁶. A further area of investigation includes the use of bioadhesive polymers in buccal delivery systems. Bioadhesive polymers have been developed to adhere to a biological substrate in order to maintain continual contact of an agent with the site of delivery. This process has been termed mucoadhesion when the substrate is mucosal tissue^37,
38.

8.2 Hydrogels:

Another type of nanotechnology revolves around the use of "hydrogels" as carriers of drugs. The principle behind this technology is to use a chemical compound which traps a drug and then releases the active compound by "swelling" or expanding inside of specific tissues, thus allowing a higher concentration of the drug in a biodegradable format. Hydrogels are very specialized systems and are generally formulated to meet specific needs for the delivery of individual drugs³⁹. Hydrogels are known for their super-absorbency and ability to form extended polymer networks through hydrogen bonding. In addition, they are excellent bioadhesive, which means that they can adhere to mucosal linings within the gastrointestinal tract for extended periods, releasing their encapsulated medications slowly over time⁴⁰.

Glucose sensitive hydrogel can be used to deliver insulin to diabetic patients using an internal pH trigger⁴¹. In a biosensor, the swelling and shrinking of the hydrogel is usually made to be responsive to changes in the level of a biological indicator or molecule of interest. This is generally achieved by incorporating into the hydrogel an enzyme, receptor, antibody, or other agent which binds the molecule of interest. Oxidoreductase enzymes are one category of such agents, which find particular use in biosensors. The characteristic of oxidoreductase enzymes of particular value in sensor applications is the production of oxygen by the enzyme reaction⁴². A pH-sensitive hydrogel containing glucose oxidase (GOx) enzyme is called a glucose-sensitive hydrogel (GSH) due to its responsiveness to environmental glucose concentrations. Thermally stable GOx is a flavin-containing glycoprotein which catalyzes a reaction which is very specific for glucose, and which produces gluconic acid and hydrogen peroxide in the presence of glucose and oxygen. Therefore, increases in the environmental glucose concentration lower the pH value within the GSH⁴³. Both insulin delivery devices and glucose biosensors, GOx stability is essential for long term use in vivo. For insulin delivery devices and the pressure based glucose biosensors, a rapid swelling kinetic is also important, to provide the best performance. The use of hydrogels containing oxidoreductase enzymes in biosensors and controlled drug delivery systems, and more particularly to the inclusion of catalase in such biosensors and drug delivery systems has been reported⁴⁴.

In-situ gelation is a process of gel formation at the site of application after the composition or formulation has been applied to the site. As a drug delivery agent, the in-situ gel has an advantage related to the gel or polymer network being formed in-situ providing sustained release of the drug agent. At the same time, it permits the drug to be delivered in a liquid form. The in-situ gelation compositions using ionic polysaccharides have been reported^{45, 46} which consist of a drug, a polymer and a gel forming ionic polysaccharide which consists of two components, an ionic polysaccharide and a cross-linking ion capable of cross-linking the former. The in-situ gel formation is induced by the application of the cross-linking ions^{47, 48}.

8.3 Dry Powder Inhaler:

Dry powder inhaler consist a pharmacologically active polypeptide and a surfactant, wherein at least 50% of the total mass of the polypeptide and the surfactant consists of primary particles having a diameter less than 10 microns. The compositions are suitable for inhalation from a dry powder inhaler device⁴⁹. It has been found that when a peptide or protein is combined with an appropriate absorption enhancer and is introduced into the lung in the form of a powder of appropriate particle size, it readily enters the pulmonary circulation by absorption through the layer of epithelial cells in the lower respiratory tract^{50, 51}. This is conveniently accomplished by inhalation of the powder from an inhaler device, which dispenses the correct dose of powdered polypeptide/enhancer in a particle size which maximizes deposition in the lower respiratory tract, as opposed to the mouth and throat. It has been found that when insulin is combined with an appropriate absorption enhancer and is introduced into the lower respiratory tract in the form of a powder of appropriate particle size, it readily enters the systemic circulation by absorption through the layer of epithelial cells in the lower respiratory tract^{52, 53}. This is conveniently accomplished by inhalation of the powder containing insulin and the absorption enhancer from an inhaler device, which dispenses the correct dose of powdered active compounds in a particle size which maximizes deposition in the lower respiratory tract, as opposed to the mouth and throat⁵⁴.

The plasma pharmacokinetics of insulin delivered by the method of the invention has been found to resemble more closely the plasma pharmacokinetics of endogenous insulin secreted by a healthy individual in response to glucose challenge or a meal, than does the plasma pharmacokinetics of human insulin delivered by subcutaneous injection, the standard route of insulin delivery. This is believed to occur because a dose of insulin delivered in accordance with the invention is absorbed much more rapidly into the systemic circulation than is a dose of subcutaneously injected insulin^{55, 56}.

The ability to deliver pharmaceutical compositions as dry powders, however, is problematic in certain respects. The dosage of many pharmaceutical compositions is often critical so it is necessary that any dry powder delivery system be able to accurately, precisely, and reliably deliver the intended amount of drug. Moreover, many pharmaceutical compositions are quite expensive. Thus, the ability to efficiently deliver the dry powders with a minimal loss of drug is critical. It is also essential that the powder be readily dispersible prior to inhalation by the patient in order to assure adequate distribution and systemic absorption⁵⁷.

8.4 Pulmonary Delivery:

Pulmonary drug delivery can itself be achieved by different approaches, including liquid nebulizers, aerosol based metered dose inhalers (MDI's), and dry powder dispersion devices. Aerosol-based MDI's are losing favor because they rely on the use of chlorofluorocarbons (CFC's), which are being banned because of their adverse effect on the ozone layer. Many otherwise labile macromolecules may be stably stored as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers⁵⁸.

Controlled release drug delivery to the lung may simplify the way in which many drugs are taken. Pulmonary drug delivery is an attractive alternative to oral, transdermal, and parenteral administration because self-administration is simple, the lungs provide a large mucosal surface for drug absorption, there is no first-pass liver effect of absorbed drugs, and there is reduced enzymatic activity and pH mediated drug degradation compared with the oral route^{59, 60}. Relatively high bioavailability of many molecules, including macromolecules, can be achieved via inhalation. As a result, several aerosol formulations of therapeutic drugs are in use or are being tested for delivery to the lung⁶¹.

Drugs currently administered by inhalation come primarily as liquid aerosol formulations. However, many drugs and excipients, especially proteins, peptides, and biodegradable carriers, are unstable in aqueous environments for extended periods of time. Considering these and other limitations, dry powder formulations (DPF's) are gaining increased interest as aerosol formulations for pulmonary delivery. However, among the disadvantages of DPF's is that powders of ultrafine particulates usually have poor flowability and aerosolization properties, leading to relatively low respirable fractions of aerosol, which are the fractions of inhaled aerosol that escape deposition in the mouth and throat^62,63. A primary concern with many aerosols is particulate aggregation caused by particle-particle interactions, such as hydrophobic, electrostatic, and capillary interactions⁶⁴. An effective dry-powder inhalation therapy for both short and long term release of therapeutics, either for local or systemic delivery, requires a powder that displays minimum aggregation. Therefore, a need exists for dry powders suitable for inhalation, which minimize or eliminate the above-mentioned problems^{65, 66}.

8.5 Transdermal delivery:

Prior art efforts to develop a non-injectable transdermal insulin delivery system for the treatment of diabetes have not been successful to date. While insulin can be systemically delivered to a patient by the topical application of an insulin containing vehicle, the systemic blood levels of insulin that are achievable using this delivery method have proven to be generally inadequate for meeting the demands of the diabetic patient ^{67, 68}. Various methods have been developed for enhancing the transdermal delivery of insulin including improved passive diffusion carriers for increasing the permeability of the epidermis, sonophoresis, iontophoresis and ionosonic transport. Passive diffusion through the outer layer of skin has been used successfully for the delivery of low molecular weight lipophilic drugs such as scopolamine, estradiol and nitroglycerine, but has been largely unsuccessful for the transdermal delivery of hydrophilic peptides such as insulin due to the low skin permeability of such peptides⁶⁹. Clinical use of transdermal drug delivery has been limited because very few drugs are able, at least by passive diffusion alone, to penetrate the skin at a sufficient rate to produce a useful systemic drug concentration in the patient^{70, 71}. The outer layer of the skin, the stratum corneum, is a major barrier to diffusion of low and especially high molecular weight drugs across the skin to the bloodstream. Insulin, unfortunately, constitutes an example of molecules which do not readily diffuse through the stratum corneum at a therapeutically useful rate. While there have been attempts in the prior art to develop transdermal patches, which contain a particular amount of insulin, which may be transferred at a particular rate⁷².

8.6 Nasal Insulin Delivery:

Nasal administration, by which a drug is transferred into circulating blood through the nasal mucosa, is being energetically studied as a method for non-injection type administration together with transdermal administration, transocular administration, transrectal administration, transpulmonary administration, etc. Among these non-injection type administration methods, the nasal administration is easy to administer a drug⁷³. Nasal administration is considered to be superior in the absorption of a drug among the non-injection type administration methods since the blood vessel system in the nasal mucous membrane is more developed compared with the skin, the ocular mucous membrane, the rectal mucous membrane etc. Therefore, a pharmaceutical preparation for nasal administration has been put into practice in some drugs. Further, the transfer of a drug into blood in nasal administration is faster than that in oral administration, and it can be expected that nasal administration has immediate effect similar to injection⁷⁴. On the other hand, the absorption of a drug through the nasal mucosa depends on physical properties such as lipophilicity of the drug and also on the molecular weight. It is pointed out that a drug having a high solubility in water, a peptide/proteinaceous drug having a large molecular weight, etc., is generally low in absorption trough the nasal mucosa. Under these circumstances, some contrivances to improve the absorption of such a drug through the nasal mucosa have been proposed⁷⁵. Chung showed the effects of penetration of thermo-sensitive gels by cross linking of chitosan on nasal delivery of insulin and they also characterized preparation by in vivo and in vitro study⁷⁶. In another study, Wang and co-workers formulated for the delivery of peptides drug through nasal delivery. They suggested that aminated gelatin microspheres increase the absorption of peptide drug⁷⁷. Takenaga and co-workers demonstrated that microparticle resins can be used for the potential nasal drug delivery system for insulin⁷⁸.

9. CONCLUSION:

There is a long history of research for development of novel routes of insulin delivery. Scientists has investigated and developed a variety of capable routes of insulin delivery, ranging from oral to rectal, with a wide variety of devices and delivery systems. Various approaches have been used to study various strategies to overcome the inherent barriers to insulin uptake across the transmucosal and transdermal routes. In recent years, the development of novel insulin delivery carriers that improve insulin absorption has thrown some promising light on the insulin therapy. Although extensive human clinical studies are still required, especially of long-term clinical applications, researchers in academic institutions and several drug delivery pharmaceutical companies are actively involved in the development of an insulin delivery system. The new millennium promises innovative change in the delivery of insulin for billions of sufferers.

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Received on 14.10.2013 Accepted on 24.10.2013

Research J. Science and Tech 5(4): Oct. - Dec., 2013 page 387-395